Every transplant organ experiences ischemia reperfusion injury (IRI). IRI evokes major intra-graft inflammatory immune responses, which augments graft immunogenicity, increases the rate of allograft rejection and markedly worsens solid organ transplantation outcomes. Reducing the deleterious effects of IRI- induced inflammatory responses has even greater clinical implications given the usage of marginal grafts as a common practice worldwide to address the shortage of organs. Nonetheless, the mechanisms by which IRI links the innate and adaptive immunity arms remain poorly explored. Our previous studies have shown that resident dendritic cells in the allografts (RDCA) play pivotal roles in linking innate and alloimmune responses. Data from our laboratory obtained using various transgenic models have led to the novel observation that increased production of IL-6 by RDCA exposed to oxidative stress leads to increased formation of CD4 alloreactive T cells in heart allografts and their respective draining lymph nodes (DLN). Intriguingly, the expression of peripheral node addressin (PNAd) molecules was markedly upregulated in the DLN of the respective ischemic organs. PNAd are adhesive molecules on the high endothelial venules of LN and play a central role in T cell homing to the LN. Use of systemic anti-IL6 therapy markedly reduced inflammatory responses in the ischemic allografts and prevented chronic rejection, which is the major obstacle to long-term acceptance of organ transplants. When we further examined the mechanism of RDCA induction by IRI, we found that IRI markedly increases autophagy in DC. Autophagy plays a key role in regulating the surface expression of MHC molecules on DC and release of inflammatory cytokines by DC. Finally, we have devised an innovative platform for the targeted delivery of immunoregulatory agents to organs and DLN to dampen the deleterious effects of IRI. With these data, the primary goal of this project is to investigate the mechanisms by which IRI enhances the immunogenicity of allografts and to identify novel protective strategies to minimize IRI, with the ultimate goal of promoting long-term allograft acceptance.
In AIM 1, we will examine the mechanisms by which RDCA promotes IRI-induced alloimmunity.
In AIM 2, we will examine the mechanism of suppression of IRI-induced alloimmunity by anti-IL-6 therapy.
In AIM 3, we will develop DLN and heart allograft targeted delivery using nanocarriers of anti-IL6 to reduce IRI-induced alloimmunity without systemic immunosuppression.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Kehn, Patricia J
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Brigham and Women's Hospital
Independent Hospitals
United States
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Uehara, Mayuko; Solhjou, Zhabiz; Banouni, Naima et al. (2018) Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity. Sci Rep 8:2461
Kasinath, Vivek; Yilmam, Osman A; Uehara, Mayuko et al. (2018) Activation of fibroblastic reticular cells in kidney lymph node during crescentic glomerulonephritis. Kidney Int :
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Azzi, Jamil; Thueson, Lindsay; Moore, Robert et al. (2017) PI3K? Deficient NOD-Mice Are Protected from Diabetes by Restoring the Balance of Regulatory to Effector-T-Cells. PLoS One 12:e0169695
Cha, Byung-Hyun; Shin, Su Ryon; Leijten, Jeroen et al. (2017) Integrin-Mediated Interactions Control Macrophage Polarization in 3D Hydrogels. Adv Healthc Mater 6:
Solhjou, Z; Uehara, M; Bahmani, B et al. (2017) Novel Application of Localized Nanodelivery of Anti-Interleukin-6 Protects Organ Transplant From Ischemia-Reperfusion Injuries. Am J Transplant 17:2326-2337
Uehara, Mayuko; McGrath, Martina M; Ohori, Shunsuke et al. (2017) Regulation of T cell alloimmunity by PI3K? and PI3K?. Nat Commun 8:951
Fischer, K; Ohori, S; Meral, F C et al. (2017) Testing the Efficacy of Contrast-Enhanced Ultrasound in Detecting Transplant Rejection Using a Murine Model of Heart Transplantation. Am J Transplant 17:1791-1801
Marino, Jose; Babiker-Mohamed, Mohamed H; Crosby-Bertorini, Patrick et al. (2016) Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation. Sci Immunol 1:aaf8759

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